Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
  • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
  • A61J1/14—Details; Accessories therefor
  • A61J1/20—Arrangements for transferring or mixing fluids, e.g. from vial to syringe
  • A61J1/2093—Containers having several compartments for products to be mixed
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
  • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
  • A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
  • A61J1/10—Bag-type containers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
  • A61L2/02—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using physical phenomena
  • A61L2/08—Radiation
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
  • A61L2/26—Accessories or devices or components used for biocidal treatment
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
  • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
  • A61J1/14—Details; Accessories therefor
  • A61J1/20—Arrangements for transferring or mixing fluids, e.g. from vial to syringe
  • A61J1/2003—Accessories used in combination with means for transfer or mixing of fluids, e.g. for activating fluid flow, separating fluids, filtering fluid or venting
  • A61J1/202—Separating means
  • A61J1/2034—Separating means having separation clips
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M2205/00—General characteristics of the apparatus
  • A61M2205/75—General characteristics of the apparatus with filters
  • A61M2205/7545—General characteristics of the apparatus with filters for solid matter, e.g. microaggregates

Definitions

• the invention relates to methods of preparing and using nutrient compositions for parenteral administration. More specifically, the invention relates to methods and uses of stable, dry-packaged, sterile, nutrient composi tions which upon addition of water are suitable for intravenous administration to mammals.
• parenteral nutrient compositions Prior hereto, commercially available parenteral nutrient compositions were generally prepared in the form of aqueous solutions employing highly sophisticated and costly manufacturing plant facilities. Because of their cost, these facilities are few in number and located long distances from the majority of sites where the solutions are required for use. Accordingly, added costs are generated by the need to transport the aqueous solutions to distant points of use such as hospitals, clinics and like medical facilities.
• the need for centralized, costly facilities for preparing parenteral nutrient compositions has been dictated by the need to prepare these compositions ready to use, i.e.; in the form of aqueous solutions meeting the stringent requirements for intravenous administration to a human.
• Patent 3,648,697 At the point of use, sterile water is mixed with the dry compositions, to form the solution at the site of use and obviate the storage and shipment of large quantities of water.
• the proposal to package and ship dry forms of parenteral compositions has not had commercial success.
• One of the major reasons for the lack of success has been the inability to produce at the site of use, an aqueous solution of the dry form, which will meet the stringent requirements of sterility, non-pyrogenieity and freedom from particulate matter. This has been due in part to a lack of a method which will provide the dry nutrient composition themselves in a state of acceptable sterility and purity.
• Even if sterile, pyrogen-free water is available at. the site of use for mixing with a dry form of the nutrient composition the product upon admixture generally has not been satisfactory, failing to meet standards.
• the method of the invention obviates a number of other problems associated with the prior art system of preparing parenteral nutrient solutions, which comprises sterilization by autoclaving.
• the parenteral solutions are packaged and then subjected to autoclaving to assure sterility.
• Autoclaving as a method of steriliza tion permits only certain nutrients to be present in the same solution during sterilization because of the chemical reactivity of these materials under autoclave conditions.
• amino acids and reducing sugars such as dextrose will combine in a Maillard reaction to form Amadori compounds which are potentially toxic and largely non-utilizable especially when infused intravenously.
• a further example of the limitation imposed by the prior art method of autoclave sterilization is encountered in regard to vitamins.
• the autoclave conditions are too severe for many vitamins such as, for example, thiamine, riboflavin, ascorbic acid and the like. These vitamins in particular are rapidly degraded to less than 10 percent of their initial activity when exposed to autoclave conditions and stored in aqueous solution, even for short periods of time.
• the dry-packaged products produced by the method of our invention greatly extend the flexible use of parenteral solutions in nutrient therapy.
• the method of our invention permits the safe, economic deliverability of simple and complex intravenous solutions at the patient's bedside.
• the invention comprises a method of preparing a stable, dry-packaged, sterile, pyrogen-free, nutrient composition for intravenous administration to a mammal, including a human, which comprises; providing the nutrient composition in a solid, form having a moisture content, which is not more than about 30 percent by weight of the solid form, provided that when the nutrient is an amino acid or carbohydrate, the moisture content does not exceed about 15 percent by weight and when the nutrient is a vitamin the moisture content does not exceed about 10 percent by weight, said form being readily dissolved in water at a temperature of circa 185°F to form an aqueous solution which will pass through a 5 micron filter by gravity at a rate of at least 1 liter per hour and the filtrate thereof will pass through a 0.22 micron filter by gravity at a rate of at least 1 liter per two hours; sealing the provided nutrient composition in a moisture-proof, microorganism-impermeable, ionizing ray permeable container adapted to receive and
• the method of the invention provides nutrient compositions in a dry-packaged form which may be admixed with sterile, pyrogen-free water suitable for parenteral use to obtain nutrient solution compositions acceptable for infusion into a human being, the compositions being solutions which are totally sterile, pyrogen-free, within acceptable limits of particulate matter and which contain nutrients, and other materials which have not been decomposed or degraded during the process of sterilization.
• the invention also comprises the storage stable, dry-packaged articles prepared by the method of the invention and the methods of their use to administer nutrients intravenously to mammals, including humans.
• sterile and "sterilizing” as used throughout the specification and claims is not according to the classical definition formulated by the Council on Pharmacy and Chemistry of the American Medical Association, but rather means the absence (or killing) of undesirable microorganisms within the limits prescribed by the United States Pharmacopia XIX (Page 592) for intravenously administerable fluid compositions.
• pyrogen-free means a material which will provide a negative reaction in the wellknown limulus test for the detection of pyrogens and which meets the requirements of the well-known rabbit test as described in the United States Pharmacopia, supra.
• ionizing-ray means ionizing radiation.
• ionizing radiation means radiation possessing an energy at least sufficient to produce ions or to break chemical bonds and thus includes also radiations such as
• the term "ionizing particle radiation” is used to designate the emission of electrons or highly accelerated, relatively heavy, nuclear particles such as protons, neutrons, alpha particles, deuterons, beta particles, or their analogs directed in such a way that the particle is projected into the mass to be irradiated.
• Charged particles can be accelerated by the aid of voltage radiants by such devices as accelerators with resonance chambers, Van der Graaff generators, insulating core transformers, betatrons, synchrotrons, cyclotrons and the like.
• Neutron radiation can be produced by bombarding a selected light metal such as beryllium with positive particles of high energy.
• Particle radiations can also be obtained by the use of an atomic pile, radioactive isotopes or other natural or synthetic radioactive materials .
• Ionizing electromagnetic radiation is produced when a metallic target such as tungsten is bombarded with electrons of suitable energy. This energy is conferred to the electrons by potential accelerators over 10,000 electron volts.
• an ionizing electromagnetic radiation suitable for the practice of this invention may be obtained by means of a nuclear reactor (pile) or by the use of natural or synthetic radioactive material, for example, cobalt 60.
• cobalt 60 as a source of ionizing radiation, producing gamma rays , is preferred in the method of the present invention.
• the term "nutrient” is employed in its usually accept ed sense as meaning a substance that nourishes; a food material. It includes within its scope sugars, minerals, vitamins, amino acids, protein hydrolyzates, oligopeptides, keto and hydroxy analogues of amino acids, starches and gelatins and the like used for plasma expansion.
• drug is employed in its usually accepted sense as meaning a therapeutic agent and it includes antibiotics, anti-coagulant, anti-arrhythmia drugs, and cancer chemotherapeutic agents and the like.
• Figure 1 is a plane view of a packaged nutrient composition prepared according to the method of the invention, together with means for intravenous administration to a mammal.
• Figure 2 is an isometric view of another embodiment packaged nutrient form of the invention.
• Figure 3 is a cross-sectional view along lines 3-3 of Figure 2.
• Figure 4 is a partial view of the embodiment package seen in Figure 3, but unfolded.
• the nutrient composition prepared by the method of the invention are represented by amino acids, dextrose, minerals including electrolytes, vitamins, mixtures thereof and like nutrient compositions. They are provided initially in the method of the invention, in solid forms having a purity acceptable, with the exception of sterility, for administration parenterally to a human. They can, of course, be initially provided in a state of sterility acceptable for parenteral administration but that is unnecessary. Essential to the method of the invention is the initial provision of the nutrient compositions having, a minimum moisture content of about 0.2 percent by weight. In the absence of this minimum, sterility may not be achieved in a satisfactory manner, i.e.; the nutrient compositions may be adversely affected or degraded.
• the maximum moisture levels will vary however, depending on the specific nutrient composition to be treated in the method of the invention. In general, the maximum allowable moisture content is about 30 percent by weight of the nutrient composition, provided that when the nutrient is an amino acid or carbohydrate the moisture content should not exceed about 15 percent by weight and should preferably be in the range of from about 4 to 8 percent by weight of the composition. When the nutrient is a vitamin, the moisture content should not exceed about 10 percent by weight of the composition and is preferably 3 percent or less. When the nutrient is a mineral the maximum moisture content should not exceed 30 percent by weight. The moisture content should preferably be 20 percent or less. If these maximum moisture contents are exceeded, there is a likelihood that the nutrient would be adversely affected, i.e.; degraded during sterilization.
• the provided nutrient composition will be free of pyrogens. This may be assured if the nutrient composition is maintained within the above-described moisture content limits as soon as possible after manufacture, until sterilized by the process of the invention.
• the initially provided nutrient composition meets the following particulate body test.
• a production lot of the nutrient composition in dry, solid form is first tumbled in a dry clean container.
• a randomly selected aliquot is removed and dissolved in a liter of hot (185°F) water and passed through a 5 micron filter by gravity.
• the liter sample should pass through the filter within one hour. If the sample does not pass this test, the starting nutrient composition is not preferred for treatment by the method of the invention.
• the 1 liter solution if it has passed the initial filter test is then passed through a 0.22 micron filter by gravity. If the filtrate passes through the 0.22 micron filter within a period of 2 hours, it is an indication that the starting nutrient composition is preferred for further processing by the method of the invention.
• the nutrient material provided for treatment by the method of the invention should also passthe USP XIX test for non-pyrogenicity.
• the initially provided nutrient compositions will have as low a bioburden as possible, i.e.; they preferably have low bacterial contamination.
• the initially provided nutrient compositions should be free of bacteria to the extent that they will exhibit a plate count of no more than 10 per gram or 1 colony per gram when tested for bacterial presence. If bacterial contamination is kept at a minimum from the time of manufacture of the nutrient composition until processed by the method of the invention, there is a likelihood that the pyrogenicity will be low.
• the initially provided nutrient compositions are then hermetically sealed in a moisture-proof, microorganism impermeable, ionizing ray-permeable container adapted to receive and dispense sterile, pyrogen-free fluids.
• the nutrient compositions are sealed in pouches, multiple containers such as overwraps or similar containers made of non-metallic materials which will effectively exclude infiltration of microorganisms, gas, vapor and moisture over a time period of several years.
• containers such as overwraps or similar containers made of non-metallic materials which will effectively exclude infiltration of microorganisms, gas, vapor and moisture over a time period of several years.
• packaging materials are commercially available in numerous forms of polymeric films, including laminates of 2 or more films.
• the pouches may be constructed of polyethylene, polypropylene, polyethyleneterephthalate, polyvinyl chloride and like polymeric films for forming hermetically sealed pouches.
• the containers should be initially provided in clean, particulate free condition and they may be pre-sterilized to some extent employing conventional techniques such as ultra-violet radiation and the like.
• a non-destructive (non-degrading), sterilizing dose of an ionizing ray as defined above is advantageously within the range of from about 0.5 to 6.0 megarads; preferably not more than 4.0. Radiation within this dosage range may be carried out at room temperature or below or at elevated temperatures if so desired. The temperature at which radiation is carried out is not critical to the method of the invention. However, practical temperatures are within the range of from about minus 10° to about 50 °C.
• the dosage employed for sterilizing the sealed in nutrient compositions is within the range of from about 1 to about 3 megarads, most preferably circa 2.5 megarads.
• the dosage of ionizing rays may be varied to some extent particularly depending on the moisture level of the material for irradiation.
• Irradiation as described about may also be carried out advantageously in the absence of oxidizing agents, i.e.; in an atmosphere having an oxygen concentration which is reduced to such a degree that the quantity of oxygen molecules present is sufficient to react during irradiation with the nutrient compositions and their packaging materials.
• the reduction of the oxygen presence can be obtained by packaging the nutrient compositions under and in the presence of an inert gaseous atmosphere such as nitrogen or by the use of partial vacuum packing.
• gamma radiation produced by cobalt 60 is a preferred ionizing ray for employment in the method of the invention.
• Gamma radiation produced by cobalt 60 has a high penetrating ability and obviates the need for concern about the thickness of the nutrient composition to be penetrated.
• a dry-package 10 which comprises a polymeric film, hermetically sealed pouch 12 containing a nutrient composition such as, for example, dextrose powder 14.
• the pouch 12 also contains at one end between dextrose powder 14 and an outlet conduit 16 a 10 micron particulate screen 18.
• An inlet conduit 20 communicates with the interior of the pouch 12 when ball valve 22 is open.
• the pouch 12 with.its contained dextrose powder 14 was hermetically sealed under vacuum conditions and irradiated with gamma radiation according to the above described method of the invention.
• sterile, pyrogen-free, water is introduced through the conduit 20, passed valve 22 via a sterile connector 24 device which may be attached to a source of sterile, pyrogen-free, water.
• a sterile connector 24 device which may be attached to a source of sterile, pyrogen-free, water.
• ball valve 22 closes and the dextrose powder 14 may be dissolved by kneading or gently shaking the pouch 12.
• Indicia may be printed on the surface of pouch 12 as shown in Figure 1, to provide an indication of volume of water introduced into the pouch 12.
• the pouch 12 may be hung up through the aperture 26 and roller clamp 28 opened to permit flow of the solution from the interior of pouch 12 through screen 18 and into the conduit 16.
• Conduit 16 may be interrupted with a drip chamber 30 and additional in-line filters such as a 0.22 micron filter 32.
• the conduit 16 may also include a "Y" type of medication injection port 34.
• An adapter and needle 36 may be fitted to the open end of conduit 16 and upon insertion of the needle 36 into a mammalian vein, the solution of dextrose is dispensed therein, controlled by clamp 28.
• an injection port 38 may be provided for mixing medications with the dissolved dextrose powder 14
• the entire pouch 12 with its preassembled conduit 16, adapter and needle 36 and other components as described above are provided in a single, hermetically sealed, bacteria-impermeable outer package wherein all parts have been sterilized by ionizing radiation as described above.
• the operator need only open the outer sterile package, remove the pouch 12 with its attached ancillary components, transfer sterile, pyrogen-free water to the interior of pouch 12 using sterile technique, affect the solution of the dextrose powder 14, make an intravenous entry of the patient with needle 36 and administer the dissolved nutrient solution employing sterile technique and conventional procedure.
• the different classes of nutritional compositions be maintained separate from each other until dissolution in aqueous medium is desired.
• amino acids and dextrose mixed together for any significant period of time will produce Maillard reactions even at moderate moisture levels and room temperature. This ultimately shortens the shelf life for the packaged, mixed nutritional composition.
• some nutritional compositions must be maintained at moisture contents differing from contents for other nutritional compositions.
• minerals are generally very hygroscopic, drawing under normal ambient conditions as much as 20 to 30 percent moisture.
• salts are also hydrates, which would tend to bring water into the interior of the hermetically sealed container.
• such minerals are segregated from the normally drier amino acids and/or dextrose materials.
• the pouch 50 comprises a polymeric film pouch quite similar to the pouch 12 previously described.
• the pouch 50 is folded once at its midsection to form a fold line 52 and secured with a "U" member54.
• Construction details of the pouch 50 may be observed by viewing Figure 3, a cross-sectional view along lines 3-3 of Figure 2.
• the fold secures pouch 50 to provide the two interior chambers 56,58 and the fold is secured by the dividing clamp member 54.
• FIG 4 one may see an isometric view-in-part of the pouch 50 as shown in Figure 2 but with the clamp member 54 removed and the pouch 50 in an open condition.
• the chambers 56, 58 are in open communication with one another.
• walls 60 and 61 are formed in the chamber 56 to form segregated sub-chambers 62, 64 and 66 within the chamber 56.
• Within the smaller chambers 62, 64 and 66 one may emplace and segregate minerals, amino acids, drugs and/or vitamins from each other within the chamber 56.
• the chamber 58 one may then place for example a carbohydrate such as dextrose.
• a single pouch 50 may be employed to effectively, contain and yet segregate from each other minerals, amino acids, vitamins and carbohydrates prior to the time when it is wished to admix them in an aqueous solution.
• the pouch 50 is similar to the package of embodiment 10 shown in Figure 1 in that there is integrally attached thereto a conduit 16, with drip chamber 30, filter 32, injection port 34, adapter and needle 36, clamp 28, conduit 20, valve 22 and sterile connection 24, all of which function as described in relation to package 10 (not all of which are shown in Figure 4).
• a conduit 16 with drip chamber 30, filter 32, injection port 34, adapter and needle 36, clamp 28, conduit 20, valve 22 and sterile connection 24, all of which function as described in relation to package 10 (not all of which are shown in Figure 4).
• one merely removes the clamping member 54 and inserts sterile, pyrogen free, particulate-free water as described in relation to the package 10.
• Administration to a human is also as described for the package 10.
• Pyrogen - representative samples are subjected to a limulus test for chemical detection of pyrogen. If positive for pyrogen by limulus, the lot is rejected. If the sample is not positive or is slightly positive for pyrogen, the sample is further tested by the rabbit test as outlined in United States Pharmacopia, XIX. If the temperatures are zero or are elevated, but under 1oC. for each of the three rabbits, the sample is accepted and passed for further processing. If the sum of temperatures in the three rabbits is higher than 3°C.,the lot is rejected. Sterility - representative samples if irradiated materials are tested by standard techniques for total plate count. Those samples that are found to be negative are then serially diluted on slant tubes in accordance with the techniques recommended in United States Pharmacopia, XIX, for sterility.
• Controls are compared with treated (irradiated) samples on a standard liquid chromatography amino acid analyzer.
• Dextrose integrity Dextrose (pure samples) are compared with treated (irradiated) samples by means of optical rotation for gross differences and silyl ester derivatives are examined by gas-liquid chromatography for degradation products.
• a flexible, polyvinyl chloride pouch type container having a capacity of 500 milliliters is selected, which has be&i. cleaned of particulate matter by washing and clean air blowing.
• Several of the pouches are each charged with 25 grams of anhydrous dextrose powder having a moisture content of 8.8 percent (Karl Fischer method) and a bacteria count of less than 10 per gram.
• the dextrose powder was selected from a production lot which was tested for particulate matter by dissolving 250 grams of the dextrose in 1,000 milliliters of hot water (185°F.) and passing the solution through a 5 micron particulate filter in less than 1 hour and passing the filtrate through a 0.22 micron air and bacteria filter by gravity in less than 2 hours.
• the lot Upon testing for pyrogens as described above, the lot is found to be pyrogen-free.
• the containers with contents of anhydrous dextrose powder are purged with nitrogen gas and sealed under vacuum, hermitically.
• the filled containers are then subjected to a cobalt 60 source until they receive a variety of radiation doses.
• the sealed, irradiated package is charged with 500 milliliters of sterile, pyrogen-free water to make a 5 percent aqueous dextrose solution. Aliquots of the solution are subjected to tests for sterility, particulate matter, degradation of nutrient composition and pyrogens.
• the radiation doses employed and the test results are shown in Table 1, below. TABLE 1
• Packages 12, 14 and 16 were tested for presence of particulate matter as described above and found to be free of particulate matter.
• Example 2 The procedure of Example 1, supra., was repeated except that the dextrose powder had a moisture content of 0.4 percent. The test results are shown in Table 2, below.
• Example 1 The procedure of Example 1, supra., was repeated except that the anhydrous dextrose as used herein was replaced with a mixture of the following minerals:
• the mixture of minerals had a moisture content of 15.8 percent. 15 grams of the mineral composition was sealed in the pouch container as described in Example 1 and irradiated. The levels of irradiation and the test results are shown in Table 3, below.
• Example 4 Following the procedure of Example 1, supra., but replacing the anhydrous dextrose as used therein with 2.5 grams of a vitamin mixture consisting of:
• Packages 4 , 6 and 8 were tested for particulate matter and found to be free of such matter.
• drugs and like medications may be included with the nutrient compositions prepared by the method of the invention; admixed therewith if compatible or segregated in a separate pouch of the container of Figure 2 if it is desired to maintain separate until use.
• Representative of such drugs are antibiotics, antifungals and the like.

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• Health & Medical Sciences (AREA)
• Public Health (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Hematology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medical Preparation Storing Or Oral Administration Devices (AREA)
• Medicinal Preparation (AREA)
• Apparatus For Disinfection Or Sterilisation (AREA)

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Family Applications (1)

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Cited By (4)

Citations (3)

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• 1981
  • 1981-08-07 GB GB8227101A patent/GB2120529B/en not_active Expired
  • 1981-08-07 WO PCT/US1981/001061 patent/WO1983000430A1/en not_active Application Discontinuation
  • 1981-08-07 JP JP50278781A patent/JPS58501226A/ja active Pending
  • 1981-08-07 EP EP19810902221 patent/EP0085045A4/de not_active Withdrawn
  • 1981-08-07 NL NL8120305A patent/NL8120305A/nl not_active Application Discontinuation
  • 1981-08-07 DE DE19813152571 patent/DE3152571A1/de not_active Withdrawn
• 1982
  • 1982-06-24 DK DK283882A patent/DK283882A/da not_active Application Discontinuation

Patent Citations (3)

Non-Patent Citations (4)

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